Hydraulic cement based on calcium phosphate for surgical use

ABSTRACT

A hydraulic cement is based on calcium phosphate for surgical use, and includes three components. The first component includes α-tricalcium phosphate powder particles. The second, component includes calcium sulphate dehydrate. The third component includes water. Furthermore the hydraulic cement does not contain more calcium sulfate hemihydrate (CSH) than 10% of the total amount of the calcium sulphate dihydrate (CSD).

This invention concerns a hydraulic cement based on calcium phosphatefor surgical use.

Calcium phosphate cements (CPC) are mixtures of one or several calciumphosphate powders that react with water to form a new calcium phosphatecompound, generally an apatite. Through these chemical reactions, thereis hardening of the aqueous paste. In vivo studies have shown that CPCare generally biocompatible, osteoconductive and somehow bioresorbable.Therefore, CPC have been the subject of a large and growing interest ofthe medical community. Several products have been introduced on themarket. However, all of these products have some drawbacks

From the U.S. Pat. No. 4,880,610 a mixture of an aqueous solution,α-tricalcium phosphate (α-TCP; Ca₃(PO₄)₂), monocalcium phosphatemonohydrate (MCPM; Ca(H₂PO₄)₂.H₂O), and calcium carbonate (CC; CaCO₃) isknown. Due to the presence of MCPM, the paste is initially acid.Therefore, dicalcium phosphate dehydrate (DCPD; CaHPO₄.2H₂O) crystalsform during the initial seconds of the setting reaction, hence renderingthe paste hard. These crystals have to be broken down to be able to keepa paste consistency and to be able to fill the bone defect with thecement paste. Hardening of the paste occurs in a second step via theformation of carbonated apatite. Due to the fact that the paste hardensin two steps, the cement cannot be mixed with a pestle and a spatula: itrequires the use of a mixing machine providing large mechanical forces(to break DCPD crystals). For the surgeon, this is obviously adisadvantage.

From the U.S. Pat. No. 5,338,356 a mixture of an aqueous solution,α-TCP, tetracalcium phosphate (TTCP; Ca₄(PO₄)₂O), dicalcium phosphate(DCP; CaHPO₄) and hydroxyapatite (HA, Ca₅(PO₄)₃OH) is known. This pastesets via one single setting reaction to form an apatite. As a result,the mixing procedure is very simple. However, the presence of a verybasic calcium phosphate (TTCP) decreases the bioresorbability of the setcement [4], which might be undesirable. Additionally, the cementformulation is rather complicated with its four different powdercomponents.

From the U.S. Pat. No. 4,518,430 a mixture of an aqueous solution, TTCPand DCP is known. As for the cement according to U.S. Pat. No.5,338,356, the use of a basic calcium phosphate (TTCP) reduces thebioresorbability of the cement. Moreover, the setting reaction is slowand must occur in the absence of blood flow.

From U.S. Pat. No. 4,619,655 it is known to use plaster of Paris(=calcium sulphate hemihydrate, CSH; CaSO₄.1/2H₂O) in combination with acalcium phosphate ceramic, such as a “calcium triphosphate”. However,these mixtures do not contain CSD. Additionally, the calcium phosphateceramic is not added as a powder but as particles. Particles larger than20 μm are not reactive enough. Therefore, the setting reaction thatcould result from the hydrolysis of α-tricalcium phosphate particleswould take a few hours which is far too long for a medical use.

From U.S. Pat. No. 5,605,713 a mixture of “three to four calciumphosphates”, in particular α-TCP is known, but none of the mentionedcalcium compounds is CSD.

From U.S. Pat. No. 5,954,867 a method is known for “making a calciumphosphate cement which self-sets at ambient temperatures comprisingcombining a calcium phosphate salt which is substantially free of TTCPwith an additional source of calcium and an aqueous solution adjustedwith a base to maintain a pH of about 12.5 or above”. Such a high basicpH-value is not desirable due to the adverse effect on the tissue cellswhich leads to a low compatibility of such a cement.

From U.S. Pat. No. 6,206,957 a “biocement paste comprising (a)tricalcium phosphate (b) at least one further calciumphosphate-containing compound, (c) a cohesion promoter and (d) a settingaccelerator, wherein components (a) and (b) form a cement powder, andcomponents (c) and (d) are in an aqueous solution, wherein said cementpowders . . . ” is known. In this patent, not only one, but two calciumphosphate compounds were used, one being α-TCP. However, no mention ofCSD is made.

In the scientific literature, Nilsson et al. (Key Eng. Mater, vols.218-220 (2202) pp 365-368) described the effects of mixing α-TCP withCSH. But again, the use of CSD is not mentioned. Although some of theCSH is hydrolysed in CSD in the presence of water so that entanglementof CSD crystals can take place this reaction has to compete with asecond reaction taking place simultaneously and which is the hydrolysisof α-TCP and entanglement of apatite crystals. The occurrence of twocompeting parallel reactions complicates the setting reaction and leadsto interactions between the two competing setting reactions, henceleading to inadequate rheological properties of the cement paste.“Inadequate” meaning that the paste requires more water to be a paste,which has a negative effect on the injectability of the cement paste andthe final mechanical properties of the cement.

From WO02/05861 LIDGREN a cement composition is known which is based onan aqueous liquid, calcium sulfate hemihydrate (CSH) as a first reactioncomponent, calcium phosphate as a second reaction component and anaccelerator for the reaction of CSH with water. Therefore, as with themixture of Nilsson, there are two simultaneous setting reactions takingplace, namely the hydrolysis of CSH and of the calcium phosphate, whichleads to inadequate rheological properties of the cement paste (badinjectability) and a hardened cement with poor mechanical properties.

It would be desirable therefore to provide a calcium phosphate cementwhich overcomes or alleviates in part or all of the above mentioneddrawbacks.

According to a broad aspect, the present invention solves the problem ofproviding a hydraulic cement based on calcium phosphate for surgical usewhich has not a very basic component such as TTCP, consists of a limitedamount of components, sets fast, and is easy to mix.

CSH has a solubility roughly 10 times larger than that of CSD.Therefore, small amounts of CSH can have a very large impact on thecement. It is therefore very important to limit the CSH amount to aminimum, namely at least 10 times lower than the CSD amount. But it ispreferable to lower this amount down to 1-2% and more preferably to 0%.Thus, a hydraulic cement according to the invention does not containmore calcium sulfate hemihydrate (CSH) than 10% of a total amount ofsaid calcium sulphate dihydrate (CSD). Preferably, the amount of calciumsulfate sulfate hemihydrate (CSH) of the cement is lower than 5%, ormore preferably 2%, of said calcium sulphate dihydrate (CSD).

The cement according to the invention comprises a first componentcomprising α-TCP powder particles, a second component comprising calciumsulphate dihydrate (CSD; CaSO₄.2H₂O) and a third component comprisingwater. α-TCP acts as the setting component whereas CSD is simultaneouslya lubricant and enables an adequate control of the Ca/P molar ratio. Inone embodiment, the cement consists of a powder/liquid formulation to bemixed, whereby (a) a powder comprises said first and second component,and (b) a liquid comprises the third component. Component (a) canadditionally comprise water-soluble phosphate salts, and component (b)can comprise a polymer. In another embodiment, the cement consists of apowder comprising said first and second component, a first viscoussolution comprising said third component, and a second solutioncomprising a contrasting agent.

CSD is a very biocompatible material. It is obtained by mixing CSH withwater. CSD has a solubility in water close to 10 mM (in calcium ions),i.e. much larger than the concentration of calcium ions in the body. Asa result, CSD implanted in a human body disappears by passivedissolution. However, as CSD is much more soluble than the solubility ofhydroxyapatite, and as the body contains a large amount of phosphateions, hydroxyapatite can precipitate around CSD implants. Precipitationcan be enhanced if hydroxyapatite crystals are already present aroundCSD crystals. In the compositions described in this patent, α-TCP istransformed in an apatitic compound. CSD crystals can therefore betransformed into hydroxyapatite:5Ca²⁺+3HPO₄ ²⁻+H₂O═Ca₅(PO₄)₃OH+4H⁺

As a result, α-TCP/CSD mixtures implanted in vivo becomes denser andstronger with the implantation time, until all CSD is dissolved.Additionally, the precipitation of hydroxyapatite provokes a slightacidification of the cement surroundings, which is positive to keep ahigh bioresorbability.

Solubility data shows that the equilibrium pH between CSD andhydroxyapatite is close to pH 4. Therefore, if the cement was placed inpure water, the equilibrium pH should tend towards this pH value. Invivo, the pH value in the cement pores will always tend to decrease toreach this low equilibrium pH value. However, the body fluids arebuffered at a pH value close to 7.4. Therefore, there will always be acompetition between the latter two reactions: (a) acidification of thecement to reach equilibrium and (b) buffering of the cement by bodyfluids.

The use of CSD has also the advantage to promote the flow properties ofthe cement paste. This improvement is characterised by the fact that theamount of mixing liquid can be reduced when the amount of CSD isincreased.

Preferably, in cement according to the invention, the first and secondcomponents are in the form of particles having an average diameterlarger than 0.1 μm. In a preferred embodiment the powder particles ofsaid first component have an average diameter inferior to 20 μm andpreferably inferior to 10 μm. Typically the average particle diameter ischosen to be 1 μm. The specific surface area (SSA) of the powderparticles of said first component is in the range of 0.05 to 10.000m²/g, or more preferably within the range of 1 to 2 m²/g.

The setting time of the cement is an important property of the cement.If the setting time is too fast, the surgeon does not have time to usethe cement before it is hard. If the setting time is too long, thesurgeon must wait until he/she can close the wound. Therefore, anintermediate setting time is desirable. Values comprised between 1 and20 minutes are in a good range. Preferable values are in the range of 2to 15 minutes, in more details in the range of 5 to 12 minutes. Thus asetting time of a cement paste according to the invention, which isobtained by mixing a first component comprising α-tricalcium phosphatepowder particles, a second component comprising calcium sulphatedihydrate (CSD) and a third component comprising water at 37° C., isbetween 1 and 20 minutes, or preferably between 2 and 15 minutes, ormore preferably between 5 and 12 minutes.

In a preferred embodiment at least one of the three cement componentscomprises a setting regulator; a setting regulator being either asetting accelerator or a setting retarder.

The setting time can be controlled by the particle size of the α-TCPpowder: the smaller the particle size, the faster the setting reaction.However, a decrease of the particle size can be difficult to achieve(especially for diameters below 1 μm). Therefore, other methods shouldbe considered. A very efficient way to accelerate the setting time is tohave large concentrations of phosphate ions in the mixing solution. Thiscan happen via two ways: (i) a soluble phosphate salt is added as apowder in the cement formulation. Upon contact with the mixing solution,the phosphate salt dissolves, and hence accelerate the chemical reaction(LeChatelier principle). (ii) a soluble phosphate salt is pre-dissolvedin the mixing liquid. Examples of soluble phosphate salts are Na₂HPO₄,NaH₂PO₄, K₂HPO₄, KH₂PO₄, NH₄H₂PO₄. Typical concentrations in the mixingliquid are in the range of 0.05 to 1.00 M. Another way to accelerate thesetting reaction is to add nuclei for apatite crystal growth, as thenucleation step of the setting reaction is a limiting factor. Typically,apatite crystals can be used, preferably a calcium-deficienthydroxyapatite or hydroxyapatite powder. Small amounts (a few weightpercents) are sufficient to drastically reduce the setting time.

When the setting time is too short, various setting additives can beadded to increase the setting time. Typical examples are compounds whichinhibits the nucleation and/or growth of apatite crystals. Commonexamples are pyrophosphate, citrate, or magnesium ions. One particularlyinteresting compound is calcium carbonate (CC; CaCO₃). Carbonate ionsare present in human bone. Additionally, carbonate ions are able toreduce the size of apatite crystals, probably via the inhibition ofapatite crystal growth.

The Ca/P molar ratio of α-TCP is 1.5. Any addition of CSD will lead toan increase of the global Ca/P molar ratio. Simultaneously, an additionof CSD will allow an additional precipitation of apatite, hence leadingto larger mechanical properties, and lower porosity. It is well-knownthat the bioresorbability of calcium phosphate cements depends on theCa/P molar ratio: an increase of the Ca/P molar ratio leads to adecrease of the bioresorption rate. Therefore, the resorbability of thecement can be controlled by the fraction of CSD used in the cementcomposition. For a low resorbability, a Ca/P molar ratio larger than 2is ideal. Thus, in a cement according to the invention, the Ca/P molarratio of the cement is greater than 1.5. Preferably the Ca/P molarration of a cement according to the invention is greater than or equalto 1.667, and more preferably is greater than or equal to 2.0.

In recent years, the occurrence of osteoporotic fractures hasdramatically increased. Considering the lack of adequate cure and theincreasing number of elderly people, this trend is expected to continue.Osteoporotic fractures are often very difficult to repair, because thebone is very weak. It is therefore not possible to insert screws to holdosteosynthesis plates. A way to solve the problem is to inject a calciumphosphate cement into the osteoporotic bone to reinforce it. In order toprevent any extravasation of the cement into the tissues surroundingbone, it is very important to visualise the cement. The easiest way isto increase the radio-opacity of the cement, for example by means ofcontrasting agents. Metallic powders of tantalum, titanium or tungsten(among others) can be used. However, it might not be desirable to usesuch powders in partially bioresorbable cements. It is preferable to useliquid agents, such as iodine compounds. Examples are iopamidol, iohexoland iotrolan.

The injection of a CPC into an osteoporotic bone is only possible if thecement is well injectable. Often, CPC are not well injectable. Thereason is a too large average particle size and a too low viscosity ofthe mixing liquid, leading to so-called filter pressing: when a pressureis applied on the cement paste (e.g. during cement injection), theliquid and solid phases are separated. The easiest way to solve theproblem is to increase the viscosity of the mixing liquid, for exampleby adding small amounts of polysaccharides into the mixing liquid.Typical polymers that can be used are polysaccharide derivativescomprising hyaluronic acid or salt, chondroitin sulphate, dermantansulphate, heparan sulphate, heparin, dextran, alginate, keratansulphate, hydroxypropylmethyl cellulose, chitosan, xanthan gum, guargum, carrageenan. The most interesting compounds are those alreadycertified for medical applications, such as hyaluronate compounds.Typical concentrations are around 1% w/w. The additive used to controlthe cement rheology can be added to any one of said three componentsused to form the cement, and can be added in an amount that is largerthat 1 weight percent (w/w) of the third component.

The viscosity of the mixing liquid is (as seen above) important toprevent filter-pressing. The viscosity of the cement paste is also avery important factor. The cement viscosity should be high enough toprevent a too fast mix with body fluids, such as blood. A mix with bodyfluids could prevent cement setting and hence lead to complications. Thepaste viscosity is also very important to prevent cement extravasationduring bone augmentation (injection of cement into bone): the larger theviscosity, the lower the risk of extravasation. Therefore, the cementviscosity should be larger than 1 Pa·s at a shear rate of 400s⁻¹, oneminute after the start of cement mixing, and preferably above 10 or even100 Pa·s at a shear rate of 400s⁻¹, one minute after the start of cementmixing.

The viscosity of the cement paste depends obviously on thepowder-to-liquid (P/L) ratio. An increase of the P/L ratio leads to aincrease of the cement viscosity. If the P/L ratio is too high, theamount of mixing liquid is too low to fill up all the pores between thedifferent solid particles, and hence to form a cement paste. The volumeof mixing liquid (VL) should be in the range of: 0.5 VT<VL<10 VT whereVT is the powder volume of the cement paste. More typical values are inthe range of 1.0 VT<VL<2.5VT. By volume is meant the real volume (andnot the apparent volume), i.e. the weight divided by the density of thematerial.

CPC particles have the disadvantage that they do not have macropores,i.e. pores larger than 50-100 μm in diameter, in which blood vessels andbone cells can grow in. As a result, the bioresorption occurslayer-by-layer and not everywhere in the cement bulk. To prevent this,bioresorbable or biodegradable granules made of calcium phosphate, CSD,polymer or bioglass whose diameter are at least two times larger thanthe average diameter of the powder particles of the first component canbe added to the first or second component of the cement paste accordingto the invention. Upon implantation, the granules will dissolve, henceleaving empty pores. Typically, these granules, e.g. CSD granules,should have an average size in the range of 100 to 500 μm, or morepreferably, in the range of 200 μm to 350 μm.

A different way to create macropores in the cement structure is toincorporate gas bubbles in the cement paste. This incorporation can bepromoted by adding a tensioactive agent. Tensioactive agents can also beused to incorporate a poorly water-soluble contrasting agent into thecement paste, for example organic iodine compounds (see above). Thetensio-active agent may be incorporated in one of said three componentsof the cement, preferably in the third component, and is preferablytaken from the group of:

docusate sodium (C₂₀H₃₇NaO₇S), sodium lauryl sulphate (C₁₂H₂₅NaO₄S),stearic acid (C₁₇H₃₅COOH), alkyldimethyl(phenylmethyl)ammonium chloride[CAS registry number 8001-54-5], benzethonium chloride (C₂₇H₄₂CINO₂),cetrimide (C₁₇H₃₈BrN), glycerin monooleate (C₂₁H₄₀O₄), polysorbate 20(C₅₈H₁₁₄O₂₆), polysorbate 21 (C₂₆H₅₀O₁₀), polysorbate 40 (C₆₂H₁₂₂O₂₆),polysorbate 60 (C₆₄H₁₂₆O₂₆), polysorbate 61 (C₃₂H₆₂O₁₀), polysorbate 65(C₁₀₀H₁₉₄O₂₈), polysorbate 80 (C₆₄H₁₂₄O₂₆), polysorbate 81 (C₃₄H₆₄O₁₁),polysorbate 85 (C₁₀₀H₁₈₈O₂₈), polysorbate 120 (C₆₄H₁₂₆O₂₆), polyvinylalcohol ((C₂H₄O)_(n)), sorbitan di-isostearate (C₄₂H₈₀O₇), sorbitandioleate (C₄₂H₇₆O₇), sorbitan monoisostearate (C₂₄H₄₆O₆), sorbitanmonolaurate (C₁₈H₃₄O₆), sorbitan monooleate (C₂₄H₄₄O₆), sorbitanmonopalmitate (C₂₂H₄₂O₆), sorbitan monostearate (C₂₄H₄₆O₆), sorbitansesqui-isostearate (C₃₃H₆₃O_(6.5)), sorbitan sesquioleate(C₃₃H₆₃O_(6.5)), sorbitan sesquistearate (C₃₃H₆₃O_(6.5)), sorbitantri-isostearate (C₃₃H₆₃O_(6.5)), sorbitan trioleate (C₃₃H₆₃O_(6.5)),sorbitan tristearate (C₃₃H₆₃O_(6.5)), glyceryl monooleate (C₂₁H₄₀O₄),isopropyl myristate (C₁₇H₃₄O₂), isopropyl palmitate (C₁₉H₃₈O₂), lanolin[CAS registry number 8006-54-0], lanolin alcohols [CAS registry number8027-33-6], hydrous lanolin [CAS registry number 8020-84-6], lecithin[CAS registry number 8002-43-5], medium chain triglycerides (no registrynumber), monoethanolamine (C₂H₇NO), oleic acid (C₁₇H₃₃COOH),polyethylene glycol monocetyl ether [CAS registry number 9004-95-9],polyethylene glycol monostearyl ether [CAS registry number 9005-00-9],polyethylene glycol monolauryl ether [CAS registry number 9002-92-0],polyethylene glycol monooleyl ether [CAS registry number 9004-98-2],polyethoxylated castor oil [CAS registry number 61791-12-6], polyoxyl 40stearate (C₉₈H₁₉₆O₄₂), polyoxyl 50 stearate (C₁₁₈H₂₃₆O₅₂),triethanolamine (C₆H₁₅NO₃), anionic emulsifying wax [CAS registry number8014-38-8], nonionic emulsifying wax [CAS registry number 977069-99-0],and sodium dodecyl sulphate (NaC₁₂H₂₅SO₄).

Quite often, bone defects are not due to a traumatic event, but to adisease, e.g. bone tumor, infection, etc . . . In these cases, it wouldbe interesting to incorporate drugs, in particular pharmaceutically orphysiologically active substances, preferably antibiotics,anti-inflammatory drugs, anti-cancer drugs, peptides, and proteins suchas growth factors.

The present invention provides a method for producing a matrix ofapatite as temporary bone replacement material, which method comprisesthe steps of:

-   -   mixing (A) a first component comprising α-tricalcium phosphate        powder particles, (B) a second component comprising calcium        sulphate dihydrate (CSD), and (C) a third component comprising        water, wherein (D) said hydraulic cement does not contain more        calcium sulfate hemihydrate (CSH) than 10% of a total amount of        said calcium suphate dihydrate (CSD) and whereby (E) said        hydraulic cement does not contain a very basic component; and    -   allowing said mixture to harden.

In one embodiment, the first and second components are pre-mixed and thethird component is added subsequently. The invention also provides atemporary bone replacement material obtained by the method, wherein saidtemporary bone replacement material comprises an apatite. In oneembodiment, the temporary bone replacement material further comprisesCSD embedded in the apatite matrix. And, the invention also providesgranules or blocks obtained by hardening the cement for in vivoimplants.

The various features of novelty which characterise the invention arepointed out with particularity in the claims annexed to and forming partof this disclosure. For the better understanding of the invention, itsoperating advantages and specific objects attained by its use, referenceshould be made to the examples and descriptive matter in which areillustrated and described preferred embodiments of the invention.

EXAMPLE 1

All the cement components were pre-heated at 37° C. for one hour. 5 gα-TCP powder (specific surface area: 0.6 m²/g), 0.8 g CSD powder (SSA:0.3 m²/g), 0.2 g hydroxyapatite powder (SSA: 48 m²/g), and 2 ml 1.0% w/whyaluronate solution (Mw=1000 kDa) were mixed for 60 seconds in a beakerusing a spatula. Afterwards, the cement paste was placed into apre-heated mould and left to harden at 37° C. The setting time of thecement was 9.3±1.1 min. The cement was placed in a phosphate buffersolution for 24 hours and tested mechanically. The compressive strengthof the cement was 22±5 MPa.

EXAMPLE 2

All the cement components were pre-heated at 37° C. for one hour. 5 gα-TCP powder (SSA: 0.6 m²/g), 3.0 g CSD powder (SSA: 0.3 m²/g), 0.2 gcalcium-deficient hydroxyapatite powder (SSA: 27 m²/g), and 2.8 ml 1.0%w/w hyaluronate solution (Mw=1000 kDa) were mixed for 60 seconds in abeaker using a spatula. Afterwards, the cement paste was placed into apre-heated mould and left to harden at 37° C. The setting time of thecement was 12.0±2.2 min. The cement was placed in a phosphate buffersolution for 24 hours and tested mechanically. The compressive strengthof the cement was 13±3 MPa.

EXAMPLE 3

All the cement components were pre-heated at 37° C. for one hour. 5 gα-TCP powder (SSA: 0.6 m²/g), 1.0 g CSD powder (SSA: 0.3 m²/g), 2.0 gCSD granules (diameter 150-250 μm, 85% apparent density), 0.2 gcalcium-deficient hydroxyapatite powder (SSA: 27 m²/g), and 2.5 ml 1.0%w/w hyaluronate solution (Mw=1000 kDa) were mixed for 60 seconds in abeaker using a spatula. Afterwards, the cement paste was placed into apre-heated mould and left to harden at 37° C. The setting time of thecement was 10.0±2.4 min. The cement was placed in a phosphate buffersolution for 24 hours and tested mechanically. The compressive strengthof the cement was 18±4 MPa.

EXAMPLE 4

All the cement components were pre-heated at 37° C. for one hour. 5 gα-TCP powder (SSA: 0.6 m²/g), 0.8 g CSD powder (SSA: 0.3 m²/g), 0.2 gcalcium-deficient hydroxyapatite powder (SSA: 27 m²/g), and 2.5 ml of asolution containing 0.2 M Na₂HPO₄ and 1.0% w/w hyaluronate (Mw=1000 kDa)were mixed for 60 seconds in a beaker using a spatula. Afterwards, thecement paste was placed into a pre-heated mould and left to harden at37° C. The setting time of the cement was 4.3±0.7 min. The cement wasplaced in a phosphate buffer solution for 24 hours and testedmechanically. The compressive strength of the cement was 28±4 MPa.

EXAMPLE 5

All the cement components were pre-heated at 37° C. for one hour. 5 gα-TCP powder (SSA: 0.6 m²/g), 0.8 g CSD powder (SSA: 0.3 m²/g), 2.4 mlof a solution containing 0.2M Na₂HPO₄ and 1.0% w/w hyaluronate (Mw=1000kDa), and 0.5 ml iopamidol solution were mixed for 60 seconds in abeaker using a spatula. Afterwards, the cement paste was placed into apre-heated mould and left to harden at 37° C. The setting time of thecement was 6.5±0.9 min. The cement was placed in a phosphate buffersolution for 24 hours and tested mechanically. The compressive strengthof the cement was 21±5 MPa.

EXAMPLE 6

All the cement components were pre-heated at 37° C. for one hour. 5 gα-TCP powder (SSA: 0.6 m²/g), 0.8 g CSD powder (SSA: 0.3 m²/g), 0.2 ghydroxyapatite powder (SSA: 48 m²/g), and 2 ml of a solution containing2.0% w/w hyaluronate (Mw=1000 kDa) and 5% w/w gentamicin sulphate weremixed for 60 seconds in a beaker using a spatula. Afterwards, the cementpaste was placed into a pre-heated mould and left to harden at 37° C.The setting time of the cement was 13.3±1.6 min. The cement was placedin a phosphate buffer solution for 24 hours and tested mechanically. Thecompressive strength of the cement was 19±4 MPa.

EXAMPLE 7

All the cement components were pre-heated at 37° C. for one hour. 5 gα-TCP powder (SSA: 0.6 m²/g), 0.8 g CSD powder (SSA: 0.3 m²/g), 0.2 gcalcium-deficient hydroxyapatite powder (SSA: 27 m²/g), 0.2 g K₂HPO₄powder, and 2.8 ml of a solution containing 1.3% w/w chondroitinsulphate (Mw=1300 kDa) were mixed for 60 seconds in a beaker using aspatula. Afterwards, the cement paste was placed into a pre-heated mouldand left to harden at 37° C. The setting time of the cement was 5.9±0.7min. The cement was placed in a phosphate buffer solution for 24 hoursand tested mechanically. The compressive strength of the cement was 25±5MPa.

EXAMPLE 8

All the cement components were pre-heated at 37° C. for one hour. 5 gα-TCP powder (SSA: 2.5 m²/g), 0.8 g CSD powder (SSA: 0.3 m²/g), 0.2 gcalcium-deficient hydroxyapatite powder (SSA: 27 m²/g), 0.2 g K₂HPO₄powder, and 2.8 ml of a solution containing 1.3% w/w chondroitinsulphate (Mw=1300 kDa) were mixed for 60 seconds in a beaker using aspatula. Afterwards, the cement paste was placed into a pre-heated mouldand left to harden at 37° C. The setting time of the cement was 5.9±0.7min. The cement was placed in a phosphate buffer solution for 24 hoursand tested mechanically. The compressive strength of the cement was 25±5MPa.

EXAMPLE 9

x g a-TCP(SSA=2.4 m2/g) were mixed with 0.37 g CSD (0.8 m2/g) and(4-0.37-x)g of calcium carbonate (CaCO3; 1.5 m2/g) where x variedbetween 3.20 and 3.63 g. The powder was then mixed with 1.5-1.7 mL of apotassium phosphate solution (0.2 M KH2PO4) and the resulting paste waskneaded for 60 seconds. Afterwards, the paste was placed into a syringewhose tip had been previously cut off and its setting time wasdetermined. The cement setting time increased gradually with an increasein CaCO3 content. The x-ray diffraction analysis (XRD) of the cementafter two days of incubation at 37 C showed that the setting reactionwas strongly slowed by the addition of CaCO3. However, the specificsurface area of the cement was strongly increased (+50% with 5% CaCO3).

EXAMPLE 10

The following pre-sterilized components, i.e. 7.26 g a-TCP (SSA=2.4m2/g), 0.74 g CSD (0.8 m2/g), 0.10 g NaH2PO4. 2.0 mL of iopamidol(organic iodine solution) and 1.2 mL of a 4% sodium hyaluronatesolution, were mixed together in a sterile and closed mixer. After 30seconds of thorough mixing, the paste was injected from the mixer intotwo 2 mL syringes. The paste present in the syringes was then injectedinto the osteoporotic vertebrae (BMD=−3.5) of a corpse. The x-rayanalysis of the vertebra showed a very good radiographical contrast, aswell as a perfect cement distribution (spherical distribution).

EXAMPLE 11

9 g a-TCP (SSA=2.4 m2/g) were mixed with 0.9 g CSD (0.8 m2/g), 2.1 g ofcalcium carbonate powder (CaCO3; 1.5 m2/g; average diameter in number:1.9 m), and 4.5 mL of a 0.1M MgSO4. 0.1M Na2HPO4, and 0.05 M Na2H2P2O7solution. After 2 minutes of mixing, the paste placed into a cylindricalform, and vibrated with a vibrator to eliminate air bubbles. The top ofthe form was then covered with a wet piece of cloth. Thirty minutesafter setting (Setting time=47 min+/−5 min), the block was unmoulded andplaced in 10 mL of phosphate buffer solution (pH 7.4, 0.15M) at 37 C for5 days. After that time, the block was dried at 60 C for 3 days and thenground (with a mortar and a pestle) and sieved. The granules in therange of 0.125 mm to 2.8 mm were collected for further use in an in vivoapplication. All operations were performed in aseptic conditions withsterile components.

EXAMPLE 12

9 g a-TCP (SSA=2.4 m2/g) were mixed with 0.9 g CSD (0.8 m2/g), 2.1 g ofcalcium carbonate powder (CaCO3; 1.5 m2/g; average diameter in number:1.9 m), 4 g of maltose crystals (0.2 mm in diameter), and 4.5 mL of a0.1M MgSO4, 0.1M Na2HPO4, and 0.05 M Na2H2P2O7 solution. After 2 minutesof mixing, the paste placed into a cylindrical form, and vibratedrapidly with a vibrator to eliminate air bubbles. The top of the formwas then covered with a wet piece of cloth. Thirty minutes after setting(Setting time=47 min+/−5 min), the block was unmoulded and placed in 50mL of phosphate buffer solution (pH 7.4, 0.15M) at 37 C for 5 days.After that time, the block was dried at 60° C. for 3 days for furtheruse in an in vivo application. All operations were performed in asepticconditions with sterile components.

1. A hydraulic cement based on calcium phosphate for surgical usecomprising: A) a first component comprising α-tricalcium phosphatepowder particles (TCP); B) a second component comprising calcium sulfatedihydrate (CSD); and C) a third component comprising water; wherein D)the cement does not contain more calcium sulfate hemihydrate (CSH) than10% of a total amount of said calcium sulfate dihydrate (CSD); E) thecement does not contain tetracalcium phosphate (TTCP); and F) at leastone of the components comprises an apatite powder as a settingaccelerator.
 2. The cement according to claim 1, wherein the cement doesnot contain more calcium sulfate hemihydrate (CSH) than 2% of the totalamount of the calcium sulfate dihydrate (CSD).
 3. The cement accordingto claim 2, wherein essentially no calcium sulfate hemihydrate (CSH) isdetectable in the cement.
 4. The cement according to claim 1, whereinthe powder particles of said first component have an average diameterless than 20 μm.
 5. The cement according to claim 1, wherein at leastone of the three cement components comprises a setting regulator.
 6. Thecement according to claim 1, wherein the first or second componentcomprises a setting accelerator.
 7. The cement according to claim 1,wherein the setting accelerator is one of a calcium-deficienthydroxyapatite and a hydroxyapatite powder.
 8. The cement according toclaim 1, wherein the setting accelerator is a water-soluble phosphatesalt selected from the group consisting of Na₂HPO₄, NaH₂PO₄, K₂HPO₄,KH₂PO₄ and NH₄H₂PO₄.
 9. The cement according to claim 1, wherein thethird component comprises a setting accelerator.
 10. The cementaccording to claim 9, wherein the setting accelerator is a dissolvedphosphate salt selected from the group consisting of Na₂HPO₄, NaH₂PO₄,K₂HPO₄, KH₂PO₄ and NH₄H₂PO₄.
 11. The cement according to claim 5,wherein the setting regulator is a setting retarder.
 12. The cementaccording to claim 1, wherein the first or second component comprises asetting retarder.
 13. The cement according to claim 12, wherein thesetting retarder is selected from the group consisting of citrate,pyrophosphate, carbonate and magnesium ions.
 14. The cement according toclaim 1, wherein a setting time of a cement paste obtained by mixingsaid three components at 37° C. is between 1 and 20 minutes.
 15. Thecement according to claim 14, wherein the setting time of the cementpaste at 37° C. is between 2 and 15 minutes.
 16. The cement according toclaim 15, wherein the setting time of the cement paste at 37° C. isbetween 5 and 12 minutes.
 17. The cement according to claim 1, wherein aCa/P molar ratio of a cement paste obtained by mixing said threecomponents is greater than 1.5.
 18. The cement according to claim 17,wherein the Ca/P molar ratio of the cement is equal to 1.667.
 19. Thecement according to claim 17, wherein the Ca/P molar ratio of the cementis greater than 1.667.
 20. The cement according to claim 17, wherein theCa/P molar ratio of the cement is greater than or equal to 2.0.
 21. Thecement according to claim 1, wherein one of the components contain aradiological contrasting agent.
 22. The cement according to claim 21,wherein the radiological contrasting agent is a liquid compound.
 23. Thecement according to claim 22, wherein the radiological contrasting agentis an organic iodine compound selected from the group consisting ofiopamidol (C₁₇H₂₂I₃N₃O₈), iohexol (C₁₉H₂₆I₃N₃O₉), and iotrolan(C₃₇H₄₈I₆N₆O₁₈).
 24. The cement according to claim 1, wherein one ofsaid three components comprises an additive to control the cementrheology.
 25. The cement according claim 24, wherein the third componentcomprises an additive to control the cement rheology.
 26. The cementaccording to claim 24, wherein the additive used to control the cementrheology is selected from the group consisting of polysaccharidederivatives comprising hyaluronic acid or salt, chondroitin sulfate,dermantan sulfate, heparan sulfate, heparin, dextran, alginate, keratansulfate, hydroxypropylmethyl cellulose, chitosan, xanthan gum, guar gum,and carrageenan.
 27. The cement according to claim 24, wherein theadditive used to control the cement rheology is hyaluronic acid and/orhyaluronic salt.
 28. The cement according to claim 24, wherein aconcentration of the additive used to control the cement rheology islarger than 1 weight percent of the third component.
 29. The cementaccording to claim 1, wherein a volume VL of the third component is inthe range of 0.5 VT≦VL≦10.0 VT where VT is total powder volume of thefirst and second component.
 30. The cement according to claim 29,wherein the volume VL of the third component is in the range of 1.0VT≦VL≦2.5 VT where VT is the total powder volume of the first and secondcomponent.
 31. The cement according to claim 1, wherein the first orsecond component of the cement may further comprise bioresorbable orbiodegradable granules whose diameter are at least two times larger thanthe average diameter of said powder particles of said first component.32. The cement according to claim 31, wherein the granules have anaverage diameter in the range of 100 μm to 500 μm.
 33. The cementaccording to claim 32, wherein the granules have an average diameter inthe range of 200 μm to 350 μm.
 34. The cement according to claim 31,wherein the granules are made of calcium phosphate, CSD, polymer orbioglass.
 35. The cement according to claim 1, wherein said first andsecond component is in the form of particles having an average diameterlarger than 0.1 μm.
 36. The cement according to claim 1, wherein one ormore of said three components comprises pharmaceutically orphysiologically active substances selected from the group consisting ofantibiotics, anti-inflammatory drugs, drugs against osteoporosis,anti-cancer drugs, peptides, and proteins.
 37. The cement according toclaim 1, wherein the one of said three components comprises atensio-active agent selected from the group consisting of: docusatesodium (C₂₀H₃₇NaO₇S), sodium lauryl sulfate (C₁₂H₂₅NaO₄S), stearic acid(C₁₇H₃₅COOH), alkyldimethyl(phenylmethyl)-ammonium chloride [CASregistry number 8001-54-5], benzethonium chloride (C₂₇H₄₂CINO₂),cetrimide (C₁₇H₃₈BrN), glycerin monooleate (C₂₁H₄₀O₄), polysorbate 20(C₅₈H₁₁₄O₂₆), polysorbate 21 (C₂₆H₅₀O₁₀), polysorbate 40 (C₆₂H₁₂₂O₂₆),polysorbate 60 (C₆₄H₁₂₆O₂₆), polysorbate 61 (C₃₂H₆₂O₁₀), polysorbate 65(C₁₀₀H₁₉₄O₂₈), polysorbate 80 (C₆₄H₁₂₄O₂₆), polysorbate 81 (C₃₄H₆₄O₁₁),polysorbate 85 (C₁₀₀H₁₈₈O₂₈), polysorbate 120 (C₆₄H₁₂₆O₂₆), polyvinylalcohol ((C₂H₄O)_(n)), sorbitan di-isostearate (C₄₂H₈₀O₇), sorbitandioleate (C₄₂H₇₆O₇), sorbitan monoisostearate (C₂₄H₄₆O₆), sorbitanmonolaurate (C₁₈H₃₄O₆), sorbitan monooleate (C₂₄H₄₄O₆), sorbitanmonopalmitate (C₂₂H₄₂O₆), sorbitan monostearate (C₂₄H₄₆O₆), sorbitansesqui-isostearate (C₃₃H₆₃O_(6.5)), sorbitan sesquioleate(C₃₃H₆₃O_(6.5)), sorbitan sesquistearate (C₃₃H₆₃O_(6.5)), sorbitantri-isostearate (C₃₃H₆₃O_(6.5)), sorbitan trioleate (C₃₃H₆₃O_(6.5)),sorbitan tristearate (C₃₃H₆₃O_(6.5)), glyceryl monooleate (C₂₁H₄₀O₄),isopropyl myristate (C₁₇H₃₄O₂), isopropyl palmitate (C₁₉H₃₈O₂), lanolin[CAS registry number 8006-54-0], lanolin alcohols [CAS registry number8027-33-6], hydrous lanolin [CAS registry number 8020-84-6], lecithin[CAS registry number 8002-43-5], medium chain triglycerides (no registrynumber), monoethanolamine (C₂H₇NO), oleic acid (C₁₇H₃₃COOH),polyethylene glycol monocetyl ether [CAS registry number 9004-95-9],polyethylene glycol monostearyl ether [CAS registry number 9005-00-9],polyethylene glycol monolauryl ether [CAS registry number 9002-92-0],polyethylene glycol monooleyl ether [CAS registry number 9004-98-2],polyethoxylated castor oil [CAS registry number 61791-12-6], polyoxyl 40stearate (C₉₈H₁₉₆O₄₂), polyoxyl 50 stearate (C₁₁₈H₂₃₆O₅₂),triethanolamine (C₆H₁₅NO₃), anionic emulsifying wax [CAS registry number8014-38-8], nonionic emulsifying wax [CAS registry number 977069-99-0],and sodium dodecyl sulfate (NaC₁₂H₂₅SO₄).
 38. The cement according toclaim 1, wherein the specific surface area (SSA) of the powder particlesof said first component is in the range of 0.05 to 10.000 m²/g.
 39. Thecement according to claim 38, wherein the specific surface area (SSA) ofthe first component is in the range of 1 to 2 m²/g.
 40. The cementaccording to claim 1, wherein a viscosity of the cement is larger than 1Pa·s at a shear rate of 400s⁻¹, one minute after the start of cementmixing.
 41. The cement according to claim 40, wherein the cementviscosity of the cement is larger than 10 Pa·s at a shear rate of400s⁻¹, one minute after the start of cement mixing.
 42. The cementaccording to claim 1, wherein the cement consists of a powder/liquidformulation to be mixed, whereby a) a powder comprises said first andsecond component; and b) a liquid comprises the third component.
 43. Thecement according to claim 1, wherein the cement consists of thefollowing parts: c) a powder comprising said first and second componentd) a first viscous solution comprising said third component; and e) asecond solution comprising a contrasting agent.
 44. The cement accordingto claim 42, wherein component a) additionally comprises water-solublephosphate salts and component b) comprises a polymer.
 45. The cementaccording to claim 1, wherein a setting time of the mixture of saidthree components is between 2 to 15 minutes.
 46. A method for producinga matrix of apatite as temporary bone replacement material, comprisingthe steps of mixing said three components of claim 1 and allowing saidmixture to harden.
 47. Method according to claim 46, wherein the firstand second component are pre-mixed and the third component is addedsubsequently.
 48. A temporary bone replacement material obtained by themethod according to claim 46, wherein said temporary bone replacementmaterial comprises an apatite.
 49. The temporary bone replacementmaterial according to claim 48, wherein said temporary bone replacementmaterial comprises CSD embedded in said apatite matrix.
 50. Granules orblocks obtained by hardening the cement according to claim 1 for in vivoimplants.
 51. A hydraulic cement based on calcium phosphate for surgicaluse comprising: a first component comprising α-tricalcium phosphatepowder particles (TCP) having an average diameter less than 20 μm; asecond component comprising calcium sulfate dihydrate (CSD); and a thirdcomponent comprising water; wherein: at least one of the first, secondor third components comprises an apatite powder as a settingaccelerator; at least one of the first, second or third componentscomprises an additive to control the cement rheology; and the cementdoes not contain more calcium sulfate hemihydrate (CSH) than 10% of atotal amount of said calcium sulfate dihydrate (CSD).